High-mobility group box-1 was released actively and involved in LPS induced depressive-like behavior
Introduction
Depression disorder is a common, chronic and life debilitating mental illness characterized by low mood, low self-esteem and disrupted sleeping, eating and cognition. According to the World Health Organization (WHO), depression disorder is one of the main causes of disability, ranking the fourth on the list of the global burden of diseases (see from url: http://www.who.int/mediacentre/factsheets/fs369/en/). However, the mechanisms underlying the pathophysiology of depression disorder remain elusive. Current researches in the spectrum of antidepressant studies mostly focus on the monoamine neurotransmitters system along with their specific reuptake and receptor protein, the functions of hypothalamic-pituitary-adrenal (HPA) axis and neurotropic system as well as neurogenesis (Blier and de Montigny, 1994, Duman et al., 1997, Duman and Monteggia, 2006). Clinical trial data suggest that at least one-third of depressed patients are non-responsive or resistant to all clinical antidepressants (Machado et al., 2006, Souery et al., 2006). This implicates the additional biological mechanisms involved in the pathogenesis of depression. The urgent need for new type of antidepressant with higher efficacy, and perhaps with fewer shortcomings, is also very strong.
As research continues, interaction between the body and the brain through the immune system became of interest in the field of research in psychiatric disorders. Activation of the inflammatory response has been observed in patients with depression disorder and depressive animal patterns (Dantzer et al., 2011, Raison et al., 2006). Studies provided strong evidence that exogenous administration of several cytokines caused depressive symptoms in human (McDonald et al., 1987, Niiranen et al., 1988). Moreover, administration of lipopolysaccharide (LPS) to animals could induce depressive-like behavior, which resembled the symptoms of depression and could be abolished by administration of antidepressant medications(e.g. imipramine) (Dunn et al., 2005, Yirmiya, 1996). Those researches proved the contribution of inflammation to the development of depression. Inflammation and pro-inflammatory cytokines may play an important role in the pathophysiology of depression as mentioned above. Therefore, it is reasonable to infer a beneficial effect of anti-inflammatory therapy on depression-like behavior.
High-mobility group box 1 protein (HMGB1) is a ubiquitous chromatin component expressed in nucleated mammalian cells. In 1990s, it was first demonstrated that stimulated mononuclear phagocytes secreted HMGB1 (Wang et al., 1999). By far, we have known that HMGB1 can be secreted actively by various immune cells and non-immune cells (e.g. macrophages, monocytes, neutrophils and neurons) in response to exogenous and endogenous inflammatory stimuli such as endotoxin, tumor-necrosis factor alpha (TNF-α), interleukin (IL)-1, interferon gamma (IFN-γ) and CpG DNA (Jiang et al., 2005, Lotze and Tracey, 2005, Sun et al., 2014). Active secretion of HMGB1 is regulated via the process involving phosphorylation, acetylation, packaging into secretory lysosomes, and exocytosis (Xu et al., 2010). In addition, damaged or necrotic nonimmune cells, apoptotic cells not included, passively release HMGB1 (Klune et al., 2008). Extracellular HMGB1 has multiple activities by binding to multiple receptors, and is involved in several processes such as inflammation, immunity, migration, invasion, proliferation, differentiation, antimicrobial defense, and tissue regeneration (Kang et al., 2014, Rauvala and Rouhiainen, 2007). HMGB1 has been functionally characterized as an “alarmin” or “danger signal” whose release from cells servers to inform adjacent (or remote) cells of infection and/or injury, so that an appropriate defensive immune response can be generated. HMGB1 is an important mediator in innate immunity, inflammation and sterile injury. As reviewed by Fleur Schaper, in different disease models like sepsis, ischemia-reperfusion and arthritis, HMGB1-blocking therapies have been tested and the disease course was shown to be ameliorated (Schaper et al., 2013). Recently, several researches reported that HMGB1 was involved in some emotional and cognitive dysfunctions such as postoperative cognitive dysfunction (POCD) (He et al., 2012, Vacas et al., 2014).
In present study, we aim to explore the role of HMGB1 in depression disorder and attempt to throw more light on the relation between inflammation, especially the late-phase mediator, and depression. In addition, glycyrrhizic acid (GZA), a compound exists in liquorice root, is used as an antagonist of HMGB1.
Section snippets
Reagents
Lipopolysaccharide (LPS, from Escherichia coli 0111:B4, Cat# L2630), recombinant human HMGB1 (rHMGB1, expressed in E. coli, purity≥90%, Cat# H4652), glycyrrhizic acid ammonium salt (GZA, from glycyrrhiza root, Cat# G2137), 4′,6-diamidino-2-phenylindole dihydrochloride (DAPI, Cat# D9542) were all obtained from Sigma (Sigma Aldrich, USA). Rabbit anti-HMGB1 antibody (Cat# ab79823) was obtained from Abcam (Abcam, UK). Fluorescein isothiocyanate (FITC) conjugated donkey anti-rabbit IgG antibody (Cat#
Serum HMGB1 level increases along with depressive behavior 24 h post LPS administration
Generally, depressive-like behavior is evaluated 16–24 h after LPS injection. This time point is chosen because previous study demonstrated that LPS could induce depressive-like behavior without inducing significant sickness behavior in mice (Capuron and Miller, 2011). As shown in Fig. 1A–B, the serum expression levels of pro-inflammatory cytokines increased significantly (A, TNF-α, t = 6.13, P < 0.01; B, IL-1β, t = 3.01, P < 0.05) 1 h post-LPS administration. This indicated the acute
Discussion
The present study shows that HMGB1 is actively released during the LPS induced depression process and establishes the important role of HMGB1 in LPS induced depressive behavior. We provide evidence that HMGB1 acts as a novel late-phase mediator that links inflammation and subsequent depressive-like behavior. In addition, this study provides more evidence for the inflammatory hypothesis of depression disorder.
Since Ader and Cohen's report in 1975 (Ader and Cohen, 1975), interaction between the
Conclusions
In conclusion, in our research we demonstrated that HMGB1, acted as a late-phase inflammation mediator, was released actively post LPS administration and was involved in LPS induced depressive-like behavior. The present study reported the depression-inducible effect of HMGB1 for the first time. Inhibition of HMGB1 may have therapeutic benefits for depression disorder.
Authors' contributions
Teng-Yun Wu established the depression model and performed the behavioral test, with the help of Lei Liu, Yi-Zhang, Xiao-Liang Shen and Yuan–Yuan Yang. Lei Liu and Wei Zhang analyzed the results and drafted the manuscript. Teng-Yun Wu and Yun-Zi Liu performed the immunohistochemical experiments. Yun-Xia Wang and Chun-Lei Jiang secured funding for the project and helped with the final version of the manuscript.
Competing interests
All authors have read and approved the final manuscript. There is no potential competing interest.
Acknowledgment
This work is supported by the Natural Science Foundation of China (NSFC, NO.81171124 and NO.81101010) and Military Medical Research Foundation (AWS11J003, BWS14J021 and 2013JS13). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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Teng-Yun Wu and Lei Liu contributed to this work equally.